A reduction in insulin-like growth factor (IGF)-I signaling has been associated with an extension in lifespan and the delayed onset of age-related disorders in diverse species. However, the underlying mechanisms of the aging process related to the IGF system remain to be determined. The IGF system is complex with ubiquitously expressed IGF receptors that mediate diverse biological outcomes. There is also a complement of IGF binding proteins (IGFBPs) and IGFBP proteases that ultimately determine ligand availability and, therefore, regulate cellular response. Recent in vitro and in vivo studies have identified a novel IGFBP protease, PAPP-A, that controls local IGF action. Our overall hypothesis is that the aging process in mammals is regulated by IGFBPase/PAPP-A. IGFBPase/PAPP-A is a secreted protein that degrades an inhibitory IGFBP thereby increasing IGF-I available for receptor activation. Thus, interventions that decrease IGFBPase/PAPP-A expression or inhibit its proteolytic activity (thereby decreasing IGF-I bioavailability) should increase longevity. Our data in IGFBPase/PAPP-A knock-out mice strongly support this tenet, i.e., genetic deletion of IGFBPase/PAPP-A extends both the mean and maximum lifespan of mice. It will be important to understand the mechanisms underlying this longevity in order to establish a scientific basis for potential development of anti-aging therapies targeting an extracellular regulator of IGF-I action, IGFBPase/PAPP-A. Towards this goal, the Specific Aims of the proposal are to: 1) Determine mortality rates and age-related pathologies in wild-type and IGFBPase/PAPP-A knock-out mice, 2) Define the mechanistic components (e.g., metabolism, antioxidant defenses, mitochondrial DNA damage) associated with the extended lifespan of IGFBPase/PAPP-A knock-out mice, 3) Determine if IGFBPase/PAPP-A deficiency affects immune competence, and 4) Assess the contribution of IGFBPase/PAPP-A deficiency during fetal development to extended lifespan. The proposed studies seek to gain a better understanding of IGFBPase/PAPP-A and the IGF system in the fundamental biology of aging, with implications for novel strategies to slow the aging process and increase quality lifespan in humans.